2-carboxy-4-oxo-4h,10h-(2)-benzopyrano-(4,3-g)-(1)-benzopyrans and salts thereof

ABSTRACT

WHEREIN R1 is hydrogen or lower alkyl, R2, R4 and R5, which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxyl, lower alkoxy, acyloxy, halogen, nitro or -SO3H, and R3 and R6, which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxyl, lower alkoxy, acyloxy, halogen, nitro, -SO3H, hydroxycarbonyl-methoxy, Beta -hydroxy-ethoxy or Beta -amino-ethoxy, AND SALTS THEREOF; THE COMPOUNDS AS WELL AS THE SALTS ARE USEFUL AS ANTIALLERGICS.   Compounds of the formula   D R A W I N G

United States Patent [191 Devlin et al.

[451 Aug. 26, 1975 2-CARBOXY-4-OXO-4I-I,l0H-(2)- BENZOPYRANO-[4,3-G]-(1)- BENZOPYRANS AND SALTS THEREOF [73] Assignee: Boehringer Ingelheim GmbH,

Ingelheim am Rhine, Germany [22] Filed: Aug. 28, 1973 [21] Appl. No.: 392,182

[30] Foreign Application Priority Data Aug. 29, 1972 Austria 7425/72 [52] US. Cl. 260/345.3; 424/283 [51] Int. Cl. C07D 311/78 [58] Field of Search 260/3453 [56] References Cited UNITED STATES PATENTS 3,741,990 6/1973 Nelson 260/3453 FOREIGN PATENTS OR APPLICATIONS 740,548 4/1970 Belgium Primary ExaminerJohn M. Ford Attorney, Agent, or Firm-Hammond & Littell ABSTRACT Compounds of the formula wherein R is hydrogen or lower alkyl,

R R and R which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxyl, lower alkoxy, acyloxy, halogen, nitro or --SO II, and

R and R which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxyl, lower alkoxy, acyloxy, halogen, nitro, SO H, hydroxycarbonyl-methoxy, B-hydroxy-ethoxy or B-amino-ethoxy,

and salts thereof; the compounds as well as the salts are useful as antiallergics.

5 Claims, No Drawings wherein R, through R have the same meanings as in formula I, with an oxalic acid ester, especially a dilower alkyl oxalate.

The reaction is preferably carried out in a basic, nonaqueous medium, such as sodium alcoholate. The reactants are advantageously first dissolved or suspended in a non-aqueous solvent, such as ethanol, and the solution or suspension is introduced into the basic medium at room temperature or while gently warming. The rewherein action mixture is then refluxed for some time, and, R is hydrogen or lower alkyl, 25 after cooling, the raw condensation product is refluxed R R and R which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxyl, lower alkoxy, acyloxy, halogen, nitro or --SO H, and

R and R which may be identical to or different 30 from each other, are each hydrogen, lower alkyl,

hydroxyl, lower alkoxy, acyloxy, halogen, nitro,

B-hydroxy- 45 Method A By reacting a 2-acetyl-3-hydroxy-6H- dibenzo[b,d]pyran of the formula in acetic acid, preferably in the presence of an aqueous mineral acid, such as concentrated hydrochloric acid.

Method B By treating a 6H-dibenzo[b,d]pyranyl-(3)-fumaric acid ether of the formula -C=Ci-l-COOH II COOH I) wherein R through R have the same meanings as in formula I, with a strong mineral acid, preferably sulfuric acid. The dibenzopyranyl-fumaric acid ether is dissolved in the mineral acid, the solution is allowed to stand at room temperature, and the reaction mixture is worked up in conventional manner.

The free acid obtained as the desired end product in methods A and B may, if desired, be converted into a salt thereof with a base, such as the sodium salt. For this purpose the free acid is dissolved or suspended in water, and then the desired base is added to the solution or suspension until it has a pH of 7. The resulting solution of the salt is then preferably freeze-dried, because of the possibility that the salt may decompose if the solution thereof is evaporated.

The starting compounds of the formula II for method A are accessible, for example, by

a. the Fries arrangement [K. Fries et al., Berichte 41, 4271 (1908); and, ibid. 43, 212 (1910) of the acetic acid ester (V) of a phenol (IV) in the pres- 4H,lOH-(2)-benzopyrano-[4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-7,8-dimethoxy-10, l0-dimethyl-4I-I,

H-(2)-benzopyrano- [4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-7 ,9-dimethoxyl 0, l O-dimethyl- 4H, 1 OI-I-(2)-benzopyrano-[4,3-g]-( 1 )-benzopyran, 2-carboxy-4-oxo-l0,l0-di-n-butyl-4H,10I-l-(2)- benzopyrano-[4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-7-bromo-8-methoxy-10,10-

dimethyl-4H, 1 0H-( 2)-benzopryrano-[4,3-g]-( l ence of aluminum chloride; or 10 benzopyran, b. direct acetylation of a phenol (IV) with acetic 2-carboxy-4-oxo-5,10,10-trimethyl-4l-I,l0H-(2)- acid/boron trifluoride, pursuant to the following benzopyrano-[4,3-g]-( l )-benzopyran, schematic reaction sequences: 2-carboxy-4-oxo-8-nitrol 0,10-dimethyl-4H, 10H- R R5 (c5 0 R CCH fi (I) A phenol of the formula IV in turn is obtained, when R is to be hydrogen, by reduction with diboraneborontrifluoride or, when R, is to be lower alkyl, by Grignard alkylation of a corresponding lactone of the formula R i R R H (VI where R through R; have the meanings previously defined.

A lactone of the formula VI may be prepared from a correspondingly substituted o-bromo-benzoic acid with the aid of a suitable resorcinol derivative pursuant to the method of W. R. H. I-Iurtley, J. Chem. Soc. 1929, page 1870.

A fumaric acid pyranyl ether of the formula III may, for example, be prepared by reacting a phenol of the formula IV with dimethylacetylene-dicarboxylic acid in a basic medium.

By means of the above methods and procedures the following 2-carboxy-4-oxo-benzopyranobenzopyrans or their salts may be prepared:

2-Carboxy-4-oxo-4I-I, l 0H-(2 )-benzopyrano[4,3-g]- l )-benzopyran, 2-carboxy-4-oxol 0, l 0-dimethyl-4I-l, lOI-I-( 2)- benzopyrano-[4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-8-fluoro-10,10-dimethyl-4H,lOI-I- (2)-benzopyrano-[4,3-g]-6L)-benzopyran, 2-carboxy-4-oxo-8-chloro10,10-dimethyl-4H,10H-

(2)-benzopyrano-[4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-7-chloro-lO,l0-dimethyl-4I-I,1OH-

(2)-benzopyrano-[4,3-g]-( l )-benzopyran, 2-carboxy-4-oxo-8-methoxyl 0, lO-dimethyl- (2)-benzopyrano-[4,3-g]-( 1 )-benzopyran, and 2-carboxy-4-oxo-8-sulfo-10,10-dimethyl-4I-I,1OH

(2)-benzopyrano-[4,3-g]-( l )-benzopyran.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 2-Carboxy-4-oxo-4I-I, 0H-(2 )-benZopyrano-[4, 3-g]- (l)-benzopyran by method A A suspension of 3.8 gm (0.016 mol) of 2-acetyl-3- hydroxy-6I-I-dibenzo[b,d]pyran (m.p. 128130C) in a mixture consisting of 4.3 gm (0.029 mol) of diethyl oxalate and 60 ml of ethanol was stirred all at once into a solution of 3.3 gm (0.145 mol) of sodium in 60 ml of ethanol at 55C, and the resulting mixture was refluxed for minutes. Thereafter, the reaction mixture was cooled to 15C, and the solid raw condensation product was filtered, dried and refluxed for 30 minutes in a mixture of 53 ml of acetic acid and 20 ml of concentrated hydrochloric acid. Subsequently, the reaction mixture was cooled and then filtered, and the filter cake was purified by dissolving it in a saturated aqueous sodium bicarbonate solution, re-precipitating it therefrom with 2N hydrochloric acid, and recrystallizing it twice from aqueous dimethylsulfoxide. 2.6 gm (56% of theory) of the compound of the formula with a melting point of 30931 1C were obtained.

EXAMPLE 2 2-Carboxy-4-oxo-10,10-dimethyl-4H,10l-1-(2)- benzopyrano-[4,3-g]-( 1 )-benzopyran by method B A mixture consisting of 2.2 gm (0.01 mol) of 3-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran and 1.4 gm (0.01 mol) of dimethyl acetylene-dicarboxylate was heated on a steam bath, and four drops of benzyl trimethylammonium hydroxide were added thereto. The reddish-brown oil formed thereby was heated on the steam bath for 20 minutes more, and was then admixed with a solution of 1.1 gm (0.027 mol) of sodium hydroxide in 6 ml of water and 3.2 ml of methanol. The resulting mixture was heated for 40 minutes at 80C, then diluted with 100 ml of water, adjusted to pH 7.5 with 2N phosphoric acid and extracted twice with 50 ml of ether each. The aqueous phase was acidified to pH 4 and was then extracted four times with 50 ml of ether each. The combined ethereal extracts contained the desired 6,6-dimethyl-6H- dibenzo[b,d]pyranyl-( 3 )-fumaric acid ether, which was precipitated as and purified in conventional manner by way of its diethanolamine salt, yielding 2.2 gm (48% of theory) of the salt which had a melting point of l70l75C.

1.6 gm of 6,6-dimethyl-6H-dibenzo[b,d]pyranyl-(3)- fumaric acid ether, obtained by acidifying the diethanolamine salt produced in the preceding step, were dissolved in 50 ml of concentrated sulfuric acid, and the solution was allowed to stand at room temperature for 16 hours. Thereafter, the reaction mixture was poured over 300 gm of ice, and the mixture was filtered. The filter cake was dissolved in 2N aqueous sodium carbonate, and the resulting solution was adjusted to pH 8 with 2N phosphoric acid and then extracted with chloroform. The aqueous phase was now brought to pH 4.5 with 2N phosphoric acid and was then extracted three times with 50 ml each of a mixture of chloroform and methanol (9:1). The combined extracts were dried, the solvent was evaporated, and the residue was recrystallized from aqueous dimethylsulfoxide, yielding 748 mgm (51% of theory) of the compound of the formula which had a melting point of 247250C (decomp.).

EXAMPLE 3 2-Carboxy-4-oxol 0, l0-di-n-butyl-4H, 1 0H-( 2 benzopyrano-[4,3-g]-(1)-benzopyran by method A A solution of 5.5 gm (0.016 mol) of 2-acetyl-3- hydroxy-6,6-di-n-butyl-6H-dibenzo[b,d]pyran (an oil) and 4.2 gm (0.028 mol) of diethyl oxalate in 50 ml of ethanol was stirred all at once into a solution of 3.2 gm

(0.14mol) of sodium in 75 ml of ethanol at 43C, and the resulting mixture was refluxed for 30 minutes and then cooled to C. The solid reaction product formed thereby was isolated, dried, admixed with 43 ml of acetic acid and 17.5 ml of concentrated hydrochloric acid, and the mixture was refluxed for 50 minutes. Thereafter, the reaction mixture was allowed to cool, and the raw reaction product was collected and recrystallized twice from aqueous dimethylsulfoxide, yielding 2.2 gm (35% of theory) of 2-carboxy-4-oxo-10,10-di-nbutyl-4H, 1 01-1-( 2 benzopyrano-[4,3-g]-( l )-benzopyran having a melting point of 230232C (sintering beginning at 225C).

EXAMPLE 4 2-Carboxy-4-oxo-8-methoxyl 0, 1 0-dimethyl-4H, 10H- (2)-benzopyrano-[4,3-g]-( l )-benzopyran by method A A solution of 300 mgm (0.001 mol) of 2-acetyl-3- hydroxy-6,6-dimethyl-8-methoxy-6H- dibenzo[b,d]pyran (an oil) and 0.27 gm (0.018 mol) of diethyl oxalate in 4 ml of ethanol was added all at once to a stirred solution of 0.21 gm (0.009 mol) of sodium in 6 ml of ethanol at 50C, and the resulting mixture was refluxed for 30 minutes and then cooled to 10C. The raw condensation product was coilected, dried, admixed with 2.3 ml of acetic acid and 0.83 ml of concentrated hydrochloric acid, and the mixture was refluxed for minutes. Thereafter, the reaction mixture was cooled, and the insoluble yellow crystals formed thereby were collected by filtration and recrystallized from methanol, yielding mgm (48% of theory) of the compound of the formula 0 H C OH H O 11 C CH which had a melting point range of 230-274C.

Analysis: c n o Calculated: C 68.18%; H 4.58%; Found: C 67.96%; H 4.74%

EXAMPLE 5 2-Carboxy-4-oxo-8-chloro-10,10-dimethyl-4H, 10H- (2)-benzopyrano-[4,3-g]-( 1 )-benzopyran by method A A suspension of 3.3 gm (0.011 mol) of 2-acetyl-3- hydroxy-6,6-dimethyl-8-chloro-6H-dibenzo[b,d]pyran (m.p. 204205C) in a mixture of3.0 gm (0.0205 mol) of diethyl oxalate and 45 ml of ethanol was stirred all at once into a solution of 2.3 gm (0.1 mol) of sodium in 55 ml of ethanol at 45C, and the resulting mixture was refluxed for 20 minutes and then cooled to 8C. The solid raw condensation product formed thereby was collected, dried, admixed with 32 ml of acetic acid and l 1.5 ml of concentrated hydrochloric acid, and the mixture was refluxed for 45 minutes. Thereafter, the reaction mixture was cooled to 25C, filtered, and the filter cake was recrystallized from aqueous dimethylsulfoxide, yielding 2.1 gm (54% of theory) of the compound of the formula which had a melting point of 304-306C.

EXAMPLE 6 2-Carboxy-4-oxo-7-ch1oro-1 0,10-dimethyl-4H, 1 H- (2)-benzopyrano-[4,3-g]-( )-benzopyran by method A A suspension of 730 mgm (0.0024 mol) of 2-acetyl- -hydroxy-6,6-dimethyl-9-ch1oro-6l-ldibenzo[b,d]pyran (m.p. 172-175C) in a mixture consisting of 670 mgm (0.0046 mol) of diethyl oxalate and 8 ml of ethanol was stirred all at once into a solution of 550 mgm (0.024 mol) of sodium in ethanol at 45C, and the resulting mixture was refluxed for 20 minutes and then cooled'to C. The solid raw condensation product was collected, added to a mixture of 8 mo of acetic acid and 3 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for 1 hour. Thereafter, the reaction mixture was cooled, and the insoluble light-brown crystals formed thereby were collected and recrystallized from aqueous dimethylsulfoxide, yielding 390 mgm (46% of theory) of -carboxy-4-oxo-7-chloro-10,10-dimethyl-4l-l,10l-l,-(2)- benzopyrano-[4,3-g]-(1)-benzopyran which had a melting point of 290-292C.

EXAMPLE 7 2-Carboxy-4-oxo-7,8-dimethoxy-10,10-dimethyl- 4H,10H-(2)-benzopyrano-[4,3-g]-( 1 )-benzopryan by method A A suspension of 270 mgm (0.82 millimols) of 2- acetyl- 3-hydroxy-6,6-dimethyl-8,9-dimethoxy-6l-ldibenzo[b,d]pyran in a mixture of 8 ml of ethanol and 238 mgm (1.63 millimols) of diethyl oxalate was stirred into a solution of 200 mgm (8.7 millimols) of sodium in 4 ml of ethanol at 40C, and the resulting mixture was refluxed for 40 minutes and then cooled to 10C. The raw, insoluble condensation product (400 mgm) was collected, dried, added to a mixture of 2.2 ml of acetic acid and 0.9 ml of concentrated hydrochloric acid, and the mixture was refluxed for one hour. Thereafter, the reaction mixture was cooled, and the raw, insoluble reaction product was collected, washed with water, and recrystallized twice from methanol, yielding 180 mgm (58% of theory) of the compound of the formula H CO 8 which had a melting point of 294295C.

EXAMPLE 8 2-Carboxy-4-oxo-7-bromo-8-methoxy-10,10-dimethyl- 41-1,10l-l-(2)-benzopyrano-[4,3-g]-( l )-benzopyran by method A A suspension of 3.0 gm (0.008 mol) of 2-acetyl-3- hydroxy-6 ,6-dimethy1-8-methoxy-9-bromo-10H- dibenzo[b,d]pyran in a solution of 2.2 gm (0.015 mol) of diethyl oxalate in ethanol was poured at C into a solution of 1.6 gm (0.07 mol) of sodium in ethanol, and the resulting mixture was refluxed for 45 minutes and then cooled to about 10C. The solid, raw condensation product was collected, added to a mixture of 17.5 ml of acetic acid and 14 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for three hours. Thereafter, the reaction mixture was cooled, and the precipitate formed thereby (2.3 gm; 67% of theory) was collected; it was identified to be a mixture of the compound named in the heading and its ethyl ester. This mixture was suspended in ml of water, the suspension was treated for 10 minutes at room temperature with 10 ml of aqueous 10% ethanolamine solution, the solution obtained thereby was filtered, the filtrate was acidified with 6N hydrochloric acid, and the precipitate formed thereby was collected and recrystallized from dimethylsulfoxide, yielding 1.4 gm (41% of theory) of the compound of the formula 3 OH H300 H 0 CH3 which had a melting point of 312-318C.

EXAMPLE 9 2-Carboxy-4-oxo-8-fluoro-10,10-dimethyl-4H,10H- (2)-benzopyrano-[4,3-g]-( 1 )-benzopyran by method A A suspension of 13.5 gm (b 0.047 mol) of 2-acetyl-3- hydroxy-6,6-dimethyl8-fluoro-6Hdibenzo[b,d]pyran in a solution of 12.5 gm (0.0860 mol) of diethyl oxalate in 100 m1 of ethanol was stirred all at once into a solution of 9.6 gm (0.41 mol) of sodium in 200 ml of ethanol at 75C, and the mixture was refluxed for 15 minutes and then cooled to about 10C. The solid, raw condensation product was collected, dried, added to a mixture of 103 ml of acetic acid and 41 ml of hydrochloric acid, and the resulting mixture was refluxed for 30 minutes. Thereafter, the reaction mixture was cooled, and the solid, raw reaction product (8.0 gm) precipitated thereby was collected and washed with water; an additional 2.0 gm of the raw product were obtained upon letting the mother liquor stand for some time. The combined batches of raw product (10 gm) were stirred for 5 minutes at room temperature with a solution of 1.8 gm (0.03 mol) of ethanolamine in 100 ml of water, the insoluble matter was filtered off, the filtrate was aciditied with hydrochloric acid, and the precipitate formed thereby was collected, washed, dried and recrystallized from methanol, yielding 6.2 gm (39% of theory) of 2- carboxy-4-oxo-8-fluoro-l0,10-dimethyl-4H,10H-(2)- benzopyrano-[4,3-g]-( l )-benzopyran having a melting point of 29'7-300C.

EXAMPLE l 2-Carboxy-4-oxo-5 l0, 10-trimethyl-4l-l, 1 Ol-l-( 2 benzopyrano-[4,3-g]-( l )-benzopyran by method A A solution of 1.41 gm (0.005 mol) of 1,6,6- trimethyl-2-acetyl-3-hydroxy-6l-l-dibenzo[b,d]pyran and 1.4 gm (0.009 mol) of diethyl oxalate in 20 ml of ethanol was poured into a solution of 1.15 gm (0.05 mol) of sodium in 40 ml of ethanol at 45C, while stirring, and the resulting mixture was refluxed for three hours and then cooled to C. The precipitate formed thereby was collected, yielding 0.15 gm of the sodium salt of the raw condensation product.

The residual ethanolic solution was acidified with an excess (60 ml) of 2N hydrochloric acid, and the acidic solution was extracted three times with 50 ml each of ether. The combined ethereal extracts were washed three times with 20 ml of each of water, dried over sodium sulfate, and the solvent was evaporated, leaving 1.9 gm of the free phenolic form of the raw condensation product.

The sodium salt and the free phenolic form of the raw condensation product were separately refluxed for one hour with a mixture of acetic acid and hydrochloric acid, and each reaction mixture was then cooled to C. The raw, insoluble reaction product from each batch was collected, and the two products were combined and recrystallized three times from ethanol, yielding 1.08 gm (65% of theory) of the compound of the formula which had a melting point of 281285C.

EXAMPLE ll 2-Carboxy-4-oxo-8-hydroxyl0,10-dimethyl-4l-l,10l-l- (2)-benzopyrano-[4,3-g]( 1)-benzopyran by method A A suspension of 5 gm (0.0176 mol) of 2-acetyl-3,8- dihydroxy-10,lO-dimethyl-6H-dibenzo[b,d]pyran in a mixture of 30 ml of ethanol and 4.7 gm (0.032 mol) of diethyl oxalate was added to a solution of 4 gm (0.17 mol) of sodium in 70 ml of ethanol at 75C, and the resulting mixture was refluxed for 40 minutes and then cooled to 12C. The precipitated raw condensation product was collected, dried and added to a mixture of 38.6 ml of acetic acid and 15.7 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for 30 minutes. Thereafter, the reaction mixture was cooled, and the precipitate formed thereby was collected, yielding 2.15 gm of a substance which was identified to be a mixture of the compound named in the heading and the ethyl ester thereof. The mixture was treated with 100 ml of aqueous 2N sodium carbonate solution for 10 minutes at room temperature, and then 1.0 gm of the insoluble ester was filtered off, and the filtrate was acidified with 6N hydrochloric acid. The precipitate formed thereby was collected and recrystallized from aqueous dimethylsulfoxide, yielding 1.15 gm (20% of theory) of the compound of the formula H C CH3 which had a melting point of 305308C.

EXAMPLE 1 2 A mixture consisting of 500 mgm (0.0015 mol) of -carboxy-4-oxo-8-hydroxy-10,l0-dimethyl-4H,1OH- (2)-benzopyrano-[4,3-g]-( l )-benzopyran (see preceding example) and 1 gm (0.01 mol) of acetic acid anhydride containing 5% sulfuric acid was heated for 10 minutes at C. Thereafter, the reaction mixture was cooled and suspended in 10 ml of ether, and the precipitate formed thereby was collected by filtration, washed with water and recrystallized from ethyl acetate, yielding 340 mgm (65% of theory) of the pale yellow crystalline compound of the formula 113C CH which had a melting point above 340C (decomp. 260C) Despite the undefinitive melting point, the end product was found to be analytically and spectroscopically pure.

Analysis: C H O Calculated: C 66.31%; H 4.24%; Found: C 65.99%; H 4.08%

EXAMPLE 1 3 2-Carboxy-4-oxo-8-nitro-10, l0-dimethyl-4l-l, l 0H-(2)- benzopyrano-[4,3-g]-( l )-benzopyran 11 yielding 2.6 gm (45% of theory) of the compound of the formula which had a melting point of 293300C.

EXAMPLE l4 2-Carboxy-4oxo-8-sulfo-10,10-dimethyl-4H 1 H-( 2 benzopyrano-[4,3-g]-( l )-benzopyran A solution of 5 gm (0.0155 mol) of 2-carboxy-4-oxol0,l0-dimethyl-4H,1OI-l-(2)-benzopyrano-[4,3-g]-( l benzopyran in 92 gm of concentrated sulfuric acid was allowed to stand for five days at room temperature. Thereafter, the reaction mixture was poured over 100 gm of ice, and the resulting aqueous mixture was made alkaline with aqueous 50% sodium hydroxide. The alkaline solution was then adjusted to pH 6 with 2N phosphoric acid, and was then extracted with chloroformmethanol (9:1to remove unreacted starting material. The aqueous phase was adjusted to pH 1 with 4N hydrochloric acid, and the precipitate formed thereby was collected and recrystallized first from dimethylsulfoxide/acetic acid/ether and then from water, yielding 1.3 gm (21% of theory) of the compound of the formula which had a melting point above 350C (decomp. 290C).

The compounds of the present invention, that is, those embraced by formula I above and their salts, have useful pharmacodynamic properties. More particularly, they exhibit antiallergic activity in warm-blooded animals, such as rats.

The antiallergic activity of the compounds of the instant invention was ascertained by the so-called PCA- test (passive cutaneous anaphylaxis test) and compared to the antiallergic activity of the known related compound 1,3-bis- (2 '-carboxy-chromon-5 '-yloxy )-2-hydroxy-propane.

In this test the skin of adult laboratory rats is passively sensitized by means of intradermal injections of egg albumin/ B. Pertussis antiserum of exponentially decreasing concentrations, i.e. undiluted, 1:3, 1:9, 1:27, etc. One day later the control group rats received 5 mgm of egg albumin dissolved in 1 ml of 0.25% Evans Blue in sterile salt solution intravenously and the test group received as well varying concentrations of the test compound with the above. 25 to 30 minutes after administration of the dye and the test compound the animals are killed, and the area of blue coloration on the inside surface of the skin is measured in mm'. The PCA-titer is the reciprocal value of that serum dilution at which a blue coloration with a diameter of at least 5 mm is just barely discernable. The reduction in the PCA-titer is a measure of the degree of suppression of allergic reactions, in the present case against albumin, produced by the test compound.

The following table shows the results obtained from this test for 2-carboxy-4-oxo-l0,10-dimethyl-4H,1OH- (2)-benzopyrano-[4,3-g]-(l)benzopyran (I), which is representative of the genus embraced by the formula I, in comparison to the .known antiallergic 1,3-bis-(2- carboxy-chromon-S '-yloxy)-2-hydroxy'propane (II):

These values clearly show that the compound of the instant invention is a significantly more effective antiallergic than the known compound.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals topically, perorally, parenterally or by the respiratory route as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, emulsions, syrups, suppositories and the like. One effective parenteral or inhalation dosage unit of the compounds according to the present invention is from 0.083 to 0.84 mgm/kg body weight, and the peroral dosage range is from 0.83 to 8.4 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 1 5 Tablets The tablet composition is compounded from the following ingredients:

Sodium salt of 2-carboxy-4-oxo-l0,l0-

3-g]-( l )-benzopyran 0.l00 parts Stearic acid 0.0l0 Dextrose l .890

Total 2.000 parts Preparation:

The ingredients are admixed in conventional manner, and the mixture is compressed into 2.0 gm tablets, each of which contains 100 mgm of the benzopyranobenzopyran salt and is an oral dosage unit composition with effective antiallergic action.

EXAMPLE 16 Ointment The ointment composition is compounded from the following ingredients:

Sodium salt of 2-carboxy-4-oxo-l0,l0-

dimcthyl-4H, lOH-( 2 )-ben7.opyrano-[ 4,

3-g]-( l )-benzopyran 2000 parts Fuming hydrochloric acid 0.01 l Sodium pyrosulfite 0.050 Mixture (l:l of cctyl alcohol and stearyl alcohol 20.000 White Vaseline 5.000 Synthetic bergamot oil 0.075 Distilled water q.s.ad l00.000

Preparation:

The ingredients are uniformly blended in conventional manner into an ointment, 100 gm of which contain 2.0 gm of the benzopyrano-benzopyran salt. The ointment is an effective antiallergic composition for topical application.

EXAMPLE 1? Inhalation aerosol The aerosol composition is compounded from the following ingredients:

Sodium salt of 2-carboxy-4-oxo-l0,l0-

dimcthyl-4H, 1 H-( 2 )-benzopyrano-[ 4,

3-g]-( l )-bcnzopyran L00 parts Soybean lecithin 0.20 Propellcnt gas mixture (frigen l l,

12 and I4) q.s.ad 100.00

Preparation:

The ingredients are compounded in conventional manner, and the composition is filled into aerosol containers with a metering valve which releases 5 to mgm of active ingredient per actuation of the valve. The aerosol spray is a dosage unit composition with effective antiallergic action for administration by the respiratory route.

EXAMPLE 1 8 Hypodermic solution The solution is compounded from the following ingredients:

Sodium salt of 2-carboxy-4-oxo-l0,l0-

dimethyl-4H, I OH-( 2 )-benzopyrano-[4,

3-g]-( l )-ben7.opyran 50.0 parts Sodium pyrosulfite l.0 Sodium salt of EDTA 0.5 Sodium chloride 8.5 Doubledistilled water q.s.ad l000.()

Preparation:

The individual ingredients are dissolved in a sufficient amount of double-distilled water, the solution is diluted to the indicated concentration with the additional double -distilled water, the resulting solution is filtered until free from suspended particles, and the filtrate is filled under aseptic conditions into 1 ml- 7 other benzopyrano-benzopyrans embraced by formula l or a salt thereof is substituted for the particular active ingredient in Examples 15 through 18. Likewise, the

amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula wherein R is hydrogen or lower alkyl,

R R and R are each hydrogen, lower alkyl, hy'

droxyl, lower alkoxy, lower alkanoyloxy, halogen, nitro or SO H, and

R and R are each hydrogen, lower alkyl, hydroxyl,

lower alkoxy, lower alkanoyloxy, halogen, nitro, SO H, hydroxycarbonyl-methoxy, B-hydroxyethoxy or B-amino-ethoxy,

or a salt thereof.

2. A compound of claim 1, wherein R is hydrogen, or methyl,

R is hydrogen or methoxy,

R is hydrogen, chlorine, fluorine, hydroxyl, me-

thoxy, acetoxy, nitro or sulfo,

R is hydrogen, chlorine bromine or methoxy,

R is hydrogen, or methyl, and

R is hydrogen, or an alkali metal salt thereof.

3. A compound of claim 2 which is 2-carboxy-4-oxolO,l0-dimethyl-4H,l0l-l-(2)-benzopyrano-[4,3-g]-( l benzopyran or the sodium salt thereof.

4. The compound of claim 2 which is 2-carboxy-4- oxo- 10, 10-dimethyl-4l-l, lOH-(2)-benzopyrano-[4,3-g]- l )-benzopyran.

5. The compound of claim 2 which is the sodium salt of 2-carboxy-4-oxol 0, l 0-dimethyl-4l-l, 1 0H-( 2 benzopyrano-[4,3-g]-( l )-benzopyran.

O UNITED STATES PATENT OFFICE :"Wfif I '1 "1 (IhnihICATE ()F COR LELLTION Patent No. 3,901,925 Dated August 975 Invenmfls) JOHN DER/LIN, PATRICK BRIAN STETIART and KURT FPE'IER It is certified that error appears in the above-identified patent and that said Letters Patent are *hereby corrected as shown below:

Col. 3 Line .7 "arrgngement" should read rearrehgement Col. 7 Line 17 Before the word "-hydroxy" insert -3 Col. 7 Line 25 "8 mo" should read 8 Col. 7" Line Bl Before the word "-carboxy" insert 2 Col. 10 Line 2 Before the word "-carboxy" insert 2 Signed and Sealed this sixth D y of January 1976 [SEAL] Arrest:

RUTH c MASON c. MARSHALL DANN Arresting Officer Commissioner oj'Parents and Trademarks x 5 g 

1. A COPOUND OF THE FORMULA
 2. A compound of claim 1, wherein R1 is hydrogen, or methyl, R2 is hydrogen or methoxy, R3 is hydrogen, chlorine, fluorine, hydroxyl, methoxy, acetoxy, nitro or sulfo, R4 is hydrogen, chlorine bromine or methoxy, R5 is hydrogen, or methyl, and R6 is hydrogen, or an alkali metal salt thereof.
 3. A compound of claim 2 which is 2-carboxy-4-oxo-10,10-dimethyl-4H,10H-(2)-benzopyrano-(4,3-g)-(1)-benzopyran or the sodium salt theReof.
 4. The compound of claim 2 which is 2-carboxy-4-oxo-10,10-dimethyl-4H,10H-(2)-benzopyrano-(4,3-g)-(1) -benzopyran.
 5. The compound of claim 2 which is the sodium salt of 2-carboxy-4-oxo-10,10-dimethyl-4H,10H-(2)-benzopyrano-(4,3-g)-(1) -benzopyran. 